4-[3-(Substituted amino)-2-hydroxypropoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriols

ABSTRACT

Compounds having the formula ##STR1## wherein R 1 , R 2  and R 3  are hydrogen or acyl, and R 4  is lower alkyl having utility in the treatment of coronary diseases.

SUMMARY OF THE INVENTION

Compounds having the formula ##STR2## are useful in the treatment ofcoronary diseases. In formula I, and throughout the specification, thesymbols are as defined below.

R₁, R₂ and R₃ are the same or different and are hydrogen or acyl, withthe proviso that if they are acyl, they are the same acyl group; and

R₄ is lower alkyl.

The term "acyl", as used throughout the specification, refers to groupshaving the formula ##STR3## wherein X can be a straight or branchedchain alkyl group having 1 to 11 carbon atoms, an aryl group, or anaryl-lower alkyl. Exemplary acyl groups are acetyl, propionyl, butyryl,isobutyryl, hexanoyl, heptanoyl, decanoyl, dodecanoyl, benzoyl, o-tolyl,p-nitrobenzoyl, phenylacetyl, 3-phenylpropionyl,3-(p-chlorophenyl)butanoyl, and the like.

The term "lower alkyl" as used throughout the specification, includesboth straight and branched chain alkyl groups having 1 to 8 carbonatoms; lower alkyl groups having 1 to 4 carbon atoms are preferred.

The term "lower alkoxy", as used throughout the specification, refers togroups having the formula YO-- wherein Y is lower alkyl as definedabove.

The term "aryl", as used throughout the specification, refers to phenyland phenyl substituted with one or two lower alkyl, lower alkoxy,halogen, or nitro groups.

The term "aryl-lower alkyl", as used throughout the specification,refers to a lower alkyl group (as defined above) substituted with anaryl group (as defined above).

The term "halogen", as used throughout the specification, refers tofluorine, chlorine, bromine, and iodine.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I, and the pharmaceutically acceptable saltsthereof, are useful as antifibrillatory agents and can be used to arrestcardiac arrhythmia in mammals by the inhibition of beta adrenergicreceptors in the myocardium. For this purpose a compound of formula I,or a pharmaceutically acceptable salt thereof, may be incorporated in aconventional dosage form such as a tablet, capsule, elixir, injectableor the like, along with the necessary carrier material, excipient,lubricant, buffer, or the like. Daily doses of from about 5 to 100milligrams per kilogram of body weight, preferably about 5 to 10milligrams per kilogram of body weight can be administered in single ordivided doses as described above.

The compounds of formula I can be prepared using as a starting material1,4-diacetoxy-5,8-dihydronaphthalene, i.e., the compound having theformula ##STR4## 1,4-Diacetoxy-5,8-dihydronaphthalene is a knowncompound; see, for example, Chem. Ber., 62:2345 (1929).

The compounds of formula I include compounds wherein the R₁ O- groupsare in the cis and the trans configurations. The configuration of thefinal product is determined by the initial reaction of1,4-diacetoxy-5,8-dihydronaphthalene to yield1,4,6,7-tetrahydroxy-5,6,7,8-tetrahydronaphthalene having the formula##STR5##

trans-1,4,6,7-Tetrahydroxy-5,6,7,8-tetrahydronaphthalene can be preparedfrom the diacetate of formula II by dissolving the diacetate in aceticacid, and then treating the solution with from about 2 to about 4equivalents of silver acetate and from about 1 to about 2 equivalents ofiodine. The mixture is then heated at a temperature of from about 80 toabout 120° C for a period of from about 1 to about 24 hours undernitrogen, to yield the compound of formula III wherein the 6 and 7hydroxy groups are in the trans configuration.

cis-1,4,6,7-Tetrahydroxy-5,6,7,8-tetrahydronaphthalene can be preparedfrom the diacetate of formula II by dissolving the diacetate in aceticacid and water (from 92 to 98% acetic acid, preferably 96% acetic acid),and then treating the solution with silver acetate and iodine andheating at a temperature of from about 80° to 120° C for a period offrom about 1 to about 24 hours under nitrogen.

Prior to alkylating one of the phenolic hydroxy groups of a1,4,6,7-tetrahydroxy-5,6,7,8-tetrahydronaphthalene of formula III, it isnecessary to first protect the adjacent hydroxy groups attached to thenonaromatic ring. This can be accomplished as described in U.S. Pat. No.3,856,818 issued Dec. 24, 1974. The resulting tetrahydronaphthalene hasthe formula ##STR6## wherein R₅ and R₆ are each hydrogen, lower alkyl oraryl.

Alkylation of a compound of formula IV with epichlorohydrin yields acompound having the formula ##STR7## The reaction can be run by forminga mixture of a blocked tetrahydronaphthalenediol of formula IV andepichlorohydrin in an organic solvent such as acetone and heating themixture in an inert atmosphere. While heating, an alkali such as sodiumhydroxide is added to the mixture. The compounds of formula V are novelintermediates, and as such they constitute a part of this invention.

To prepare a compound of formula I wherein R₁, R₂ and R₃ are eachhydrogen, an oxirane compound of formula V is reacted with an alkylaminehaving the formula

    H.sub.2 N--R.sub.4                                         VI

to form an amine having the formula ##STR8## The reaction can be run inan organic solvent and is most conveniently run at ambient temperatures.Acid hydrolysis of a compound of formula VII yields the product offormula I wherein R₁, R₂ and R₃ are each hydrogen, i.e., a compoundhaving the formula ##STR9##

The compounds of formula VII are novel intermediates that constitute apart of this invention. Additionally, the compound possesses usefulpharmacological activity, and can be used to arrest cardiac arrhythmiain mammals by the inhibition of beta adrenergic receptors in themyocardium.

The products of formula I wherein R₁, R₂ and R₃ are each acyl can beprepared by first converting an amine of formula VIII to anacid-addition salt to prevent acylation of the amino group. Theacid-addition salt is then acylated using conventional techniques, e.g.,reaction with an appropriate acid anhydride or acid chloride.

The products of formula I wherein R₁ and R₂ are hydrogen and R₃ is acylcan be prepared from the corresponding compound of formula VII. Beforeproceeding with the acylation reaction it is necessary to protect thehydroxy group in the aminopropoxy side chain of the compound of formulaVII. Various means for protecting the hydroxy group will be apparent tothe practitioner of this invention. An exemplary method comprisesreacting a compound of formula VII with an aldehyde having the formula

    R.sub.7 CHO,                                               IX

wherein R₇ is lower alkyl or aryl, to yield an oxazolidine derivativehaving the formula ##STR10## The reaction can be run in an organicsolvent, preferably at the reflux temperature of the solvent. Anoxazolidine derivative of formula X can be acylated with an acidanhydride or acid chloride to yield a compound having the formula##STR11## wherein R'₃ is acyl. Hydrolysis of a compound of formula XIyields a product of formula I wherein R₁ and R₂ are hydrogen and R₃ isacyl.

The products of formula I wherein R₁ is hydrogen and R₂ and R₃ are acylcan be prepared from a compound of formula V. Reaction of a compound offormula V with a secondary amine having the formula

    H-NR.sub.4 R.sub.8,                                        XII

wherein R₈ is aryl-lower alkyl, yields a compound having the formula##STR12## The compound of formula XIII can be acylated with an acidanhydride or acid chloride to yield a compound having the formula##STR13## wherein R'₂ and R'₃ are acyl. Hydrolysis of a compound offormula XIV yields a compound having the formula ##STR14## Reduction ofa compound of formula XV, e.g., with gaseous hydrogen over a catalystsuch as palladium, yields the corresponding product of formula I whereinR₁ is hydrogen and R₂ and R₃ are acyl.

The compounds of formula I form acid-addition salts with inorganic andorganic acids. These acid-addition salts frequently provide useful meansfor isolating the products from reaction mixtures by forming the salt ina medium in which it is insoluble, and then neutralizing the salt with abase such as sodium hydroxide to obtain the free base. Any other saltmay then be formed from the free base and the appropriate inorganic ororganic acid. Illustrative are the hydrohalides, especially thehydrochloride and hydrobromide which are preferred, sulfate, nitrate,phosphate, borate, acetate, oxalate, tartrate, maleate, citrate,succinate, benzoate, ascorbate, salicyclate, methanesulfonate,benzenesulfonate, toluenesulfonate, and the like.

The following examples are specific embodiments of this invention.

EXAMPLE 1 8-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-3a,9a-cis-3a,4,9,9 a-tetrahydro-2,2-dimethylnaphtho-[2,3-d]-1,3-dioxol-5-ola. 1,4,6,7-Tetrahydroxy-5,6,7,8-tetrahydronaphthalene

To a solution of 89.2 g of 1,4-diacetoxy-5,8-dihydronaphthalene in 1.8liters of glacial acetic acid and 72 ml of water is added 106.6 g ofsilver acetate followed by 81.2 g of iodine. The resulting slurry isthen heated with stirring at 85° ± 10° C for 3 hours under nitrogen. Thereaction mixture is then cooled, filtered, and the filtrate concentratedin vacuo.

To a solution of the above residue in 1 liter of methanol at 0° C isadded a solution of 160 g of sodium hydroxide in 800 ml of water, andthe resulting mixture is stirred at room temperature overnight. Most ofthe methanol is then removed in vacuo, the resulting aqueous solution ischilled, acidified with cold concentrated hydrochloric acid, and thissolution is thoroughly extracted with n-butanol. The combined extractsare washed with saturated aqueous sodium chloride and concentrated tonear dryness in vacuo. The resulting precipitate is filtered and washedwell with ether to give 20 g of the title compound, melting point221°-224° C.

b. 5,8-Dihydroxy-3a,9-cis- 3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxole

A slurry of 19.6 g (0.10 mole) of1,4,6,7-tetrahydroxy-5,6,7,8-tetrahydronaphthalene in 250 ml of2,2-dimethoxypropane is stirred in the presence of a trace ofp-toluenesulfonic acid. Within 15 minutes almost all solid hasdissolved. After 1 hour the solution is diluted with an equal volume ofether, the resulting solution filtered through Celite to remove a smallamount of suspended matter, the filtrate washed with dilute aqueoussodium bicarbonate, dried, and concentrated in vacuo to 18 g ofcrystalline product.

c. 8-[2,3-(Epoxy)propoxy]-3a,9α 3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxol-5-ol

A stirred mixture of 18 g of 5,8-dihydroxy-3a,9-cis- 3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxole, 60 ml ofepichlorohydrin, 60 ml of acetone and 10 ml of water is heated to refluxunder nitrogen. A solution of 3.2 g of sodium hydroxide in 20 ml ofwater is then added over 15 minutes. After the addition is complete, themixture is refluxed for an additional 45 minutes.

The reaction mixture is then concentrated in vacuo (care is exercised toremove all excess epichlorohydrin to avoid further alkylation duringbase extraction), and the residue is partitioned between water andchloroform. The aqueous layer is extracted with chloroform, and thecombined chloroform extracts washed with saturated aqueous sodiumchloride, dired, and concentrated in vacuo to yield 28.8 g of oil.

The oil is combined with a previously prepared sample 6.1 g, (total=34.9g), dissolved in ethyl acetate, and thoroughly extracted with colddilute aqueous sodium hydroxide. The combined aqueous extracts arechilled, acidified with cold dilute aqueous acetic acid and theresulting solution is thoroughly extracted with ethyl acetate. Thecombined organic extracts are dried and concentrated in vacuo to 11.5 gof oil. The oil is taken up in chloroform and applied to an aluminacolumn (300 g, Activity III, neutral). Fractions 1-3 (250 ml) consist ofnon-polar material. Fractions 3-10 (250 ml) give 3.1 g of the titlecompound after concentration in vacuo, and trituration withhexane/isopropyl ether.

d. 8-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-3a,9-cis- 3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxol-5-ol

A solution of 3.1 g of 8-[2,3-(epoxy)propoxy]-3a,9a-cis- 3a,4,4,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxol-5-ol in 40 ml ofabsolute ethanol, 30 ml of benzene and 20 ml of t-butylamine is leftovernight at room temperature. The solvents are removed in vacuo toyield the title compound.

EXAMPLE 2cis-4-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,hydrochloride (1:1)

8-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-3a,9 a-cis-3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxol-5-ol, prepared abovein Example 1, is dissolved in 100 ml of 5% hydrochloric acid and left atroom temperature for 1 hour. This solution is then concentrated in vacuoto a foam. This is dissolved in hot isopropanol, decolorized withNorite, and diluted with ether. The resulting precipitate is subjectedto the same treatment to give 1.2 g of amorphous solid. The amorphousmaterial (1.2 g) is then recrystallized from isopropanol to give 0.30 gof crystalline solid, melting point 178°-185° C.

EXAMPLE 3cis-4-[2-(Acetyloxy)-3-[(1,1-dimethylethyl)amino]propoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,triacetate ester, hydrochloride (1:1)

cis-4-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriolhydrochloride (1:1) (3.62g) is added to 50 ml of trifluoroacetic acidand the resulting solution is stirred at 0°-5° C while adding 6.4 ml ofacetyl chloride dropwise. After the addition is completed, the solutionis allowed to stand at room temperature for 1 hour. The solution is thenconcentrated in vacuo, the residue diluted with aqueous sodiumbicarbonate, and then extracted with ethyl acetate. The ethyl acetateextracts are washed with saturated aqueous sodium chloride, dried, andconcentrated in vacuo. The residue is dissolved in dry ether, chilled,and treated with hydrogen chloride saturated isopropanol. The resultingprecipitate is filtered and recrystallized to yield the total compound.

EXAMPLE 4cis-4-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,1-acetate

A solution ofcis-8-[3-[(1,1-Dimethylethyl)amino]-2-hdroxypropoxy]-3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho-[2,3-d]-1,3-dioxol-5-ol (7.31 g) andbenzaldehyde (5.3g) in 100 ml of xylene is refluxed for 48 hours withconstant separation of water (Dean-Stark trap). The xylene and most ofthe excess benzaldehyde is removed in vacuo, the residue taken up in amixture of pyridine (70 ml) and acetic anhydride (30 ml), and thissolution left at room temperature for 16 hours. The pyridine and excessacetic anhydride are removed in vacuo, the residue taken up in a cold(0° C) mixture of 225 ml of 5% hydrochloric acid and 25 ml of methanol,and the reaction mixture is stirred at 0°-5° C for 2 hours. Most of themethanol is removed in vacuo and the solution is made basic with 5%aqueous sodium bicarbonate and extracted with ether. The combinedextracts are dried over magnesium sulfate and concentrated in vacuo toyield the title compound.

EXAMPLE 5cis-4-[2-(Acetyloxy)-3-[(1,1-Dimethylethyl)amino]propoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,1-acetate

A solution of 6.2g of cis-8-[2,3-(epoxy)propoxy]-3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxol-5-ol in 80 ml ofabsolute ethanol, 60 ml of benzene, and 20 ml of benzyl t-butylamine isleft at room temperature for 16 hours. The solution is taken to drynessin vacuo, the residue taken up in 70 ml of pyridine and 30 ml of aceticanhydride, and this solution is allowed to stand at room temperature for16 hours. The solution is then taken to dryness in vacuo, a cold (6° C)mixture of 225 ml of 5% hydrochloric acid and 25 ml of methanol isadded, and the mixture is stirred at 0° C for 2 hours. The solution isthen made basic with 5% aqueous sodium bicarbonate and extracted withether. The combined extracts are dried over magnesium sulfate andconcentrated in vacuo.

The above residue is dissolved in 250 ml of glacial acetic acid, oneequivalent of concentrated hydrochloric acid is added, and the resultingsolution is hydrogenated in the presence of 5g of 10% palladium/charcoalat 50-60 psi. After uptake of one equivalent of hydrogen, the catalystis filtered off and the filtrate is concentrated in vacuo to yield thetitle compound.

EXAMPLE 6 8-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-3a,9a-trans-3a ,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxol-5-ol

Following the procedure of Example 1, but substituting dry glacialacetic acid for the solution of glacial acetic acid and water in part(a), yields the title compound.

EXAMPLE 7trans-4-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,hydrochloride (1:1)

Following the procedure of Example 2, but substituting8-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-3a,9 a-trans-3a,4,9,9a-tetrahydro-2,2-diemthylnaphtho[2,3-d]-1,3-dioxol-5-ol for its cisisomer, yields the title compound.

EXAMPLE 8trans-4-[2-(Acetyloxy)-3-[(1,1-dimethylethyl)amino]-propoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,triacetate ester, hydrochloride (1:1)

Following the procedure of Example 3, but substitutingtrans-4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,hydrochloride (1:1) for its cis isomer, yields the title compound.

EXAMPLE 9trans-4-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,1-acetate

Following the procedure of Example 4, but substitutingtrans-8-[3-[(1,1-Dimethylethyl)amino]-2-hydroxypropoxy]-3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxol-5-ol for its cisisomer yields the title compound.

EXAMPLE 10trans-4-[2-(Acetyloxy)-3-[(1,1-Dimethylethyl)amino]-propoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,1-acetate

Following the procedure of Example 5, but substitutingtrans-8-[2,3-(epoxy)propoxy]-3a,4,9,9a-tetrahydro-2,2-dimethylnaphtho[2,3-d]-1,3-dioxol-5-ol for its cisisomer, yields the title compound.

EXAMPLES 11-13

Following the procedure of Example 3, but substituting the compoundlisted in column I for acetyl chloride, yields the compound listed incolumn II.

    ______________________________________                                        Column I         Column II                                                    ______________________________________                                        11. lauryl chloride                                                                              cis-4-[3-[(1,1(dimethylethyl)-                                                amino]-2-(lauryloxy)propoxy]-                                                 5,6,7,8-tetrahydro-1,6,7-naphth-                                              alenetriol, trilaurate ester,                                                 hydrochloride                                              12. o-toluyl chloride                                                                            cis-4-[3-[(1,1-dimethylethyl)-                                                amino]-2-(o-toluyloxy)propoxy]-                                               5,6,7,8-tetrahydro-1,6,7-naphth-                                              alenetriol, tri(o-toluate) ester,                                             hydrochloride                                              13. Phenylacetyl chloride                                                                        cis-4-[3-[(1,1-dimethylethyl)-                                                amino]-2-(phenylacetyloxy)propoxy]-                                           5,6,7,8-tetrahydro-1,6,7-naphth-                                              alenetriol, tri(phenylacetate)                                                ester, hydrochloride                                       ______________________________________                                    

EXAMPLES 14-17

Following the procedure of Example 4, but substituting the compoundlisted in column I for acetic anhydride, yields the compound listed incolumn II.

    ______________________________________                                        Column I         Column II                                                    ______________________________________                                        14. isobutyric anhydride                                                                         cis-4-[3-[(1,1-dimethylethyl)-                                                amino]-2-hydroxypropoxy]-5,6,7,8-                                             tetrahydro-1,6,7-naphthalene-                                                 triol, 1-isobutyrate                                       15. benzoic anhydride                                                                            cis-4-[3-[(1,1-dimethylethyl)-                                                amino]-2-hydroxypropoxy]-5,6,7,8-                                             tetrahydro-1,6,7-naphthalene-                                                 triol, 1-benzoate                                          16. p-nitrobenzoic cis-4-[3-[(1,1-dimethylethyl)-                                 anhydride      amino]-2-hydroxypropoxy]-5,6,7,8-                                             tetrahydro-1,6,7-naphthalene-                                                 triol, 1-(p-nitrobenzoate)                                 17. 3-(p-chlorophenyl)                                                                           cis-4-[3-[(1,1-dimethylethyl)-                                 butanoic anhydride                                                                           amino] -2-hydroxypropoxy]-5,6,7,8-                                            tetrahydro-1,6,7-naphthalene-                                                 triol, 1-[3-(p-chlorophenyl)-                                                 butanoate]                                                 ______________________________________                                    

EXAMPLES 18-19

Following the procedures of Examples 1 and 2, but substituting thecompound listed in column I for t-butylamine, yields the compound listedin column II.

    ______________________________________                                        Column I         Column II                                                    ______________________________________                                        18. isopropylamine cis-4-[2-hydroxy-3-(isopropyl-                                                amino)propoxy]-5,6,7,8-tetrahydro-                                            1,6,7-naphthalenetriol, hydro-                                                chloride                                                   19. methylamine    cis-4-[2-hydroxy-3-(methylamino)-                                             propoxy)-5,6,7,8-tetrahydro-1,6,-                                             7-naphthalenetriol, hydrochloride                          ______________________________________                                    

What is claimed is:
 1. A compound having the formula ##STR15## or apharmaceutically acceptable salt thereof wherein R₄ is lower alkylhaving 1 to 4 carbon atoms.
 2. A compound in accordance with claim 1wherein the OH groups are in the cis configuration.
 3. A compound inaccordance with claim 1 wherein the OH groups are in the transconfiguration.
 4. A compound in accordance with claim 1 wherein R₄ ist-butyl.
 5. The compound in accordance with claim 1 having the namecis-4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol,hydrochloride (1:1).